In contrast to the synthesis of carboxylic esters, which generally proceeds without any problem by a proton-catalyzed reaction of the free acid with an alcohol, typically with the additional use of acidic catalysts, for example sulfuric acid, hydrogen chloride gas, toluenesulonic acid or acidic ion exchangers (see, for example, Organikum, 21st edition, p. 474 ff), an esterification of a carboxylic acid group of amino acids is only possible with difficulty and with addition of the abovementioned activators or catalysts. Additionally, the esterification of the carboxylic acid group of amino acids using such a technique typically results in moderate yields (from 45 to 90%, depending on the amino acid). See, for example, G. C. Barrett, Amino Acid Derivatives (1999), 37.
The solubilities of amino acids are determined by the typical zwitterionic structure. In the solid state and in solution, a carboxylate and an ammonium group are present As a result, amino acids dissolve readily only in water, but only very slowly and with difficulty in alcohol, if at all. This considerably prolongs the reaction time in comparison to alkylcarboxylic acids.
For an esterification, the solid is initially suspended in an alcohol. Subsequently, hydrogen chloride can be passed through the mixture. See, for example, E. Fischer, Ber. Dt Chem. Ges. 39 (1906), 2893. An alternative approach is the stoichiometric addition of thionyl chloride. See, for example, M. Brenner, W. Huber, Helv. Chim. Acta 36 (1953), 1109.
In order to further increase the reaction rate, the mixture may be heated. After a few hours (or even days), the products are obtained as hydrochlorides.
It is also known that the process of azeotropic distillation can be used for the preparation of amino acid esters. This is reported, for example, in M. Dymicky, E. F. Mellon, J. Naghski, Anal. Biochem. 41 (1971), 487.
However, all of these preparation processes are time-consuming batch syntheses of the corresponding amino acid esters which can decompose as a result of reactions of the amino acid side chains under the reaction conditions required.
One method of preparing amino acid esters directly from proteins or peptides is possible according to the prior art only in a laborious process by hydrolytic cleavage (enzymatically with proteases or peptidases or chemically by acid catalysis) in a first step and subsequent esterification of the fragments. When the abovementioned prior art method is used, a multitude of by-products and a high salt burden are obtained.
There is therefore still a need for a method for the simple and inexpensive synthesis of amino acid esters and their acid addition salts, in which these products can be prepared in high space-time yields, continuously or batchwise, by direct reaction of peptides, proteins or amino acids, substantially without additions of catalysts or activators.